The interplay between host:microbial interactions is critical at mucosal surfaces. Dysregulation in these interactions can lead to intestinal inflammatory diseases, such as inflammatory bowel disease (IBD). The recognition and response to microbes is initially mediated by pattern recognition receptors (PRR). PRR responses lead to secretion of cytokines and cellular activation, as well as microbial clearance. The balance between these outcomes influences susceptibility between inflammatory diseases and infectious diseases. Our long-term goal is to understand the mechanisms mediating IBD pathogenesis, thereby ultimately improving the management and therapy of human IBD. Polymorphisms in the IRF5 region are associated with a wide-range of immune-mediated diseases, included IBD. We found that IRF5 is the single most important genetic determinant of the inter-individual variation in PRR-initiated signaling and cytokines from myeloid-derived cells across the population; carriers of the IRF5 disease risk polymorphisms secrete high levels of cytokines in response to a range of PRR stimuli. Despite the importance of IRF5 in regulating inter-individual variation in human myeloid-derived PRR-induced cytokines, the mechanism through which it contributes to PRR-initiated signaling pathways in human cells is not well defined (SA1). Key functional outcomes are modulated by time dependency of immune responses; we will examine mechanisms of rapid IRF5-mediated responses occurring via early signaling events (SA1A&B) as well as longer term, transcriptional-mediated effects (SA1C), and the modulation of these outcomes by IRF5 polymorphisms. We hypothesize that IRF5 regulates PRR-initiated signaling and outcomes in human myeloid cells through a combination of mechanisms associated with its localization in both the cytoplasm and nucleus, ultimately contributing to its broad and critical role in regulating PRRs. The consequences of IRF5 polymorphisms in differentiation of key macrophage subsets (e.g. M1 vs. M2) will be defined (SA 2A). Moreover, how IRF5 affects clearance of both resident and pathogenic intestinal microbes is not known (SA 2B). Importantly, the mechanism(s) through which IRF5 contributes to IBD pathogenesis and intestinal pathogen clearance in vivo has not been examined (SA 3). We will integrate studies in primary human cells with in vivo mouse studies to dissect IRF5 contributions to IBD pathogenesis. We hypothesize that IRF5 will contribute to multiple immune cell functions essential in intestinal immune homeostasis in vivo, and that although it may contribute to inflammatory outcomes in colitis, it is essential for regulating intestinal pathogens